The activated carbon was administered using the device described above and illustrated in the attached Figures.
Spontaneous fistula healing rates are considered to be very low, of the order of 4 to 5% (clinical experience of the participating investigators). For safety, a value of 10% was used in setting up the trial (e.g. for the subject number calculation) meaning that an uncontrolled design could be selected as the preferred design for this initial pilot trial. This design allows for a preliminary indication of effect.
Clinical assessment of fistula healing (healed/not healed), was selected as the primary endpoint since this is the endpoint used in daily clinical practice. Rectal ultrasound evaluations were also made because these can provide more detailed measures of the degree of healing as compared to the clinical evaluation (healed/not healed).
The secondary endpoints are less established, but still of importance to the evaluation of benefit/effect. It is very important to measure if the patient feels any improvement but there are no validated tools available to measure patient reported outcome in perianal fistulising disease. In this study, a VAS scale was used to assess pain and soiling, and a questionnaire was used to evaluate the impact on daily function, and also perception of ease of use.
Dose and Timing
The dose administered by the medical device in the trial was 2.6 g/day. In order to provide as much activated carbon to the affected areas as possible the device was used twice daily (with at least 6 hours in between administrations); thus, the device was used to administer activated carbon at a dose of 1.3 g twice daily.
The dose was administered by the patient in the morning: after breakfast (after defecation), and in the evening, prior to “going to bed”.
A treatment period of 8 weeks was chosen. Since the main problem with all existing treatment modalities is the high recurrence rates (20-60%), it is relevant to perform a follow up visit. In this study the follow-up visit was scheduled to be performed at least 4 months after the last administration.
Selection of the Trial Population
For this initial trial in perianal fistulas a population with few complications and low, more easily accessible, location was selected. Thirty patients were selected. The recruitment of patients was performed as described below:
1. Patients who have symptoms from their fistulas and were referred or contacted the site themself were offered an opportunity to participate in the trial.
2. Following review of patient records/data bases patients were contacted and asked to participate in the trial.
The inclusion criteria for the trial are as follows:
1. Patients with perianal fistulas diagnosed by clinical examination and evaluated as “not healed/open”
2. Fistula classified as intersphincteric and transsphincteric according to Parks' classification
3. Superficial fistula involving a part of the external sphincter muscle
4. Age: ≥18 years and ≤75 years
5. Informed consent and/or Letter of Authority (as applicable) obtained
The exclusion criteria were as follows:
6. Inflammatory Bowel Disease (IBD)
7. Rectovaginal fistulas
8. Rectouretral fistulas
9. Rectovescical fistulas
10. Extra-sphincteric and supra-sphincteric fistula according to Parks' classification
11. Complicated fistulas (eg. horse shoe fistulas) as evaluated by the investigator.
12. Any previous surgical treatment for perianal fistulas
13. Subcutaneous fistulas not involving any part of the external sphincter
14. Colorectal and/or anal malignancy
15. Other malignancy requiring active treatment
16. Other diseases which as per the investigator's opinion should be contraindicated
17. Subjects who are not able to complete study procedures as per the investigator's opinion
There are no restrictions in the therapy received prior to this trial. Anti inflammatory therapies (as NSAIDs), antibiotics or immunomodulatory concomitant therapies (including corticosteroids, metronidazole and anti TNFα therapy) were not allowed during the trial. Any other therapy for the fistula was avoided during participation in the trial.
The Investigational Medical Device (IMD) is illustrated in the attached drawings (see especially FIGS. 1 and 4) and consisted of:
1. Rectal cannula set
a. Rectal cannula with cap, valve and carbon chamber
b. Connection tube with female connector
c. Vaseline plug (soft yellow paraffin/vaselinum flavum)
d. Activated carbon 1.3 g (for injection into the rectum)
2. Sterile water (Ph. Eur. Quality) 10 ml in plastic container
3. Sterile syringe (CE-marked)—10 ml
All medical devices are provided by Nordic Drugs AB. Subjects were trained in the use of the device by the investigator or a nurse. The activated carbon (Activated Carbon 610C (EUP 2010) was administered using 10 ml. sterile water (Fresenius Kabi) by means of a sterile syringe (BRAUN Injekt, CE marked), by the method described above.
All medicinal device components were handled according to the principles of Good Manufacturing Practice and applicable ISO guidelines.
Trial Procedure
Day 1/Baseline
On day 1, consent was obtained and the patient instructed in how to use the device. The investigator performed an overall assessment of the patients state of health in order to confirm eligibility. Except for digital rectal examination and the clinical evaluation of the fistula no examinations are required. A rectoscopy was performed in order to rule out malignancies and high located fistulas. Samples were taken and sent to the local laboratory to be analysed for: CRP, Hb and WBC.
A clinical evaluation of fistula anatomy was made by anal ultrasonography.
The Form for Patient Assessment of Symptoms and Impact on Daily Function was handed out to patient and completed at the visit.
Week 2 (Telephone Visit):
By telephone interview the patients were asked if they had used the Medical Device; patients are asked if they have experienced any problems with the device and if they have observed any adverse events.
Week 8 (End of Intervention)
The investigator performed an overall assessment of the patients state of health in order to observe any possible changes (=Adverse events) not already reported by the patient. Except for digital rectal examination and the clinical evaluation of the fistula no examinations were performed.
Patients were asked if they have experienced any problems with the device and if they have observed any adverse events.
A rectoscopy was performed. Samples were taken and sent to the local laboratory to be analysed for: CRP, Hb and WBC.
A clinical evaluation of fistula closure was made by anal ultrasonography (for fistula healing and type). The Form for Patient Assessment of Symptoms and Impact on Daily Function was handed out to patient and completed at the visit. Medical Device patient acceptability/performance questions were asked.
Week 24 (Follow-Up)
A medical examination was made (digital rectal examination only), together with clinical evaluation of fistula closure by anal ultrasonography (fistula healing and type). The Form for Patient Assessment of Symptoms and Impact on Daily Function is handed out to patient and again completed at the visit.
Assessments and Results
The primary endpoint was clinical assessment of fistula healing (healed/not healed). Healing was defined as the fistula closed and no secretion as observed by visual inspection.
A rectoscopy was performed, and the result given on a scale of 1 to 5 (1=ulcerations, 2=fistula, 3=Abscess, 4=Stenosis, 5=fissure).
A Form for Patient Assessment of Symptoms and Impact on Daily Function was handed out to the patients. A 10 point VAS scale was be used to assess pain and soiling (0=no pain/soiling, 10=unbearable pain/soiling). In additions a questionnaire was used to assess the impact on daily function. The patients were also asked the following questions relating to the Medical Device at study end:
1 Would you like to use KULIST again?
If the answer is no: please explain why
2 Describe advantages and disadvantages of the device
3 Have you had any difficulties in using the device
4 Could the device be more user friendly? How?
Results
The following preliminary results are based on week 8 (end of intervention) data from 26 of the 28 enrolled patients.
Data on the primary endpoint, healing, indicates that over 30% (30.7%) have complete healing (fistula closed, no discharge). The confidence interval (data not shown) indicates the results are of statistical significance. This is a spectacular improvement on the spontaneous healing rate assessed by the clinic (4 to 5%), and is indicative that this treatment may provide a real alternative to surgery.
Oral communication with the test sites have reveiled that at least 2 other patients have, in addition experienced, improvements and signs of healing such as reduced soiling.
The patients generally found the rectal system to be easy to operate.
The only adverse event observed (1 patient) was constipation. There were no side effects or adverse events from the device itself reported. Thus, the use of rectally administered activated carbon (of specific size) is effective and avoids the drawbacks of previous methods, and the risks associated with surgical intervention.